CN112300125B - Naphthalimide-polyamine conjugate and preparation method and application thereof - Google Patents
Naphthalimide-polyamine conjugate and preparation method and application thereof Download PDFInfo
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- A61P35/00—Antineoplastic agents
Abstract
The invention discloses a naphthalimide-polyamine conjugate, the structural general formula is shown as I,
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a naphthalimide-polyamine conjugate, and a preparation method and application thereof.
Background
The naphthalimide compound as an anti-tumor small molecule is a research hotspot of medicinal chemists, and the application of the naphthalimide compound in anti-tumor medicaments is widely concerned by scientists. Many naphthalimide derivatives (such as DMP-840, Elinamide, Amonafide) have entered clinical trials, but have not been marketed due to various toxic side effects such as myelosuppression, dose limitation, blood toxicity, etc. Although the drug Amonafide (Amonafide) for treating acute myelogenous leukemia has entered clinical phase III research stage, its toxic and side effects such as myelosuppression, vomiting, rash, etc. are still difficult to reduce or eliminate. Therefore, medicinal chemists can carry out various structural modifications on naphthalimide compounds to find high-efficiency and low-toxicity naphthalimide antitumor drugs, and most of the structural modifications carried out at present are concentrated on aromatic rings of naphthalimide.
Pyrazole and quinazoline compounds are widely distributed in natural plants, are various in quantity and structure types, have wide pharmacological activities such as anti-tumor, anti-inflammatory and antibacterial, antioxidation, immunity enhancement and the like, and are hot spots of domestic and foreign research in recent years. With the intensive study on the structure-activity relationship, the study on the pyrazole and quinazoline compounds enters a new level. Pyrazole and quinazoline with various physiological activities are used as medical intermediates and are core structural fragments of a plurality of synthetic drugs. Pyrazoles and quinazolines have been found to have antitumor activity in the 60 s of the 20 th century and are less toxic when used as antitumor agents. Meanwhile, due to the variability of structural modification on the ring of the pyrazole and quinazoline, the pyrazole and quinazoline become a research hotspot in the field of antitumor in recent years.
The polyamine has multiple important physiological functions, has wide biological regulation and control effects in human bodies, and influences multiple physiological processes of cell proliferation, cell division and the like. By using a polyamine transport channel on a cell membrane, the polyamine can be used as a carrier to transport a drug into a tumor cell in a targeted manner. Meanwhile, research also shows that the polyamine modified antitumor compound can endow the compound with some new functions. Therefore, the research of polyamines on the anti-tumor aspect is attracting more and more attention.
Disclosure of Invention
In order to overcome the disadvantages of the prior art, one of the objects of the present invention is to provide a naphthalimide-polyamine conjugate, which has better inhibitory activity on tumor cells.
The second object of the present invention is to provide a process for the synthesis of the compound.
The invention also aims to provide the application of the compound in preparing antitumor drugs.
One of the purposes of the invention is realized by adopting the following technical scheme:
a naphthalimide-polyamine conjugate, which has a structural general formula I:
wherein R is phenylpyrazole or amino-quinazoline, R2Is polyamine chain, tertiary amino, hydroxyl, carboxyl or morpholinyl, q is 1, 2 or 3, and X is an integer of 0 to 4.
Further, when R is phenylpyrazole, the naphthalimide-polyamine conjugate has the structural general formula I-1:
wherein R is2Is selected from
Further, when R is an amino-quinazoline, the naphthalimide-polyamine conjugate has the general structural formula i-2:
wherein R is2Is selected from
Any one of the above.
The second purpose of the invention is realized by adopting the following technical scheme:
a method for synthesizing a compound represented by the general formula I-1, comprising the steps of:
(1) adding the compound 8 into a reaction container, and adding aluminum trichloride and acetyl chloride solution which take dichloromethane as a solvent to react to prepare a compound 9;
(2) adding the compound 9 obtained in the step (1) into a DMF-DMA solution for refluxing to prepare a compound 10, and then reacting with phenylhydrazine in an ethanol solution to prepare a compound 11;
(3) refluxing the compound 11 obtained in the step (2) with potassium dichromate under the condition that acetic acid is used as a solvent to prepare a compound 12;
(4) reacting the compound 12 obtained in the step (3) with a nitrogen-containing compound to prepare a compound 13 a-l;
(5) and (3) reacting the compound 13a-l obtained in the step (4) with 4M hydrochloric acid in absolute ethyl alcohol to obtain the naphthalimide-polyamine conjugate 14a-l with the structure of the general formula I-1.
Preferably, the synthesis route of the partial nitrogen-containing compound (or Boc anhydride protection) is as follows:
a method for synthesizing a compound represented by the general formula I-2, comprising the steps of:
(1) taking DMF-DMA as a solvent, and carrying out reflux reaction on the compound 15 to obtain a compound 16;
(2) glacial acetic acid is used as a solvent, and the compound 17 is subjected to K2Cr2O7Oxidizing to obtain a compound 18;
(3) carrying out nitration reaction on the compound 18 obtained in the step (2) in a concentrated sulfuric acid solution to obtain a compound 19;
(4) reducing the compound 19 obtained in the step (3) by tin dichloride under an acidic condition to obtain a compound 20;
(5) reacting the compound 20 obtained in the step (4) with the compound 16 obtained in the step (1) under the condition of using glacial acetic acid as a solvent to obtain a compound 21;
(6) reacting the compound 21 obtained in the step (5) with a nitrogen-containing compound to obtain compounds 22 a-d;
(7) and (3) reacting the compound 22a-d obtained in the step (6) with 4M hydrochloric acid in absolute ethyl alcohol to obtain the naphthalimide-polyamine conjugate 23a-d with the structure of the general formula I-2.
The invention also aims to provide the application of the naphthalimide-polyamine conjugate in preparing antitumor drugs.
Further, provides the application of the naphthalimide-polyamine conjugate in preparing medicaments for treating human colon cancer, liver cancer and breast cancer.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a naphthalimide-polyamine conjugate which has novel skeleton, high efficiency, low toxicity and better inhibitory activity on tumor cells. The invention also provides a preparation method of the compound, the general formula I-1 removes 3-amino group causing toxic and side effects of the aminonaphenanthrene, introduces a phenylpyrazole structural fragment on a naphthalene ring of a naphthalimide parent, and modifies an imide side chain with a polyamine chain, so that acetylation of acetyltransferase on the amino group on the aminonaphenanthrene naphthalene ring in vivo is prevented, and the toxic and side effects are reduced; and a series of naphthalimide-polyamine conjugates with novel frameworks, high efficiency and low toxicity are synthesized by introducing low-toxicity phenylpyrazole active structural fragments; the general formula I-2 is to introduce quinazoline with small toxicity to replace hydrogen atoms of 3-amino groups to obtain the naphthalimide-polyamine conjugate with anti-tumor activity and small toxicity. The invention also provides the application of the compound in preparing anti-tumor drugs, has certain inhibitory activity on human colon cancer cells, human liver cancer cells and human breast cancer cells, and shows good development potential.
Detailed Description
The present invention is further described below with reference to specific embodiments, and it should be noted that, without conflict, any combination between the embodiments or technical features described below may form a new embodiment.
Example 1
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [4-4- (4-aminobutyl) -aminobutyl ] 1H-benzisoquinoline-1, 3(2H) -dione tetrahydrochloride (14a)
(1) 1.0g (6.5mmol) of Compound 8, anhydrous AlCl was taken31.29g (9.7mmol) of the product is placed in a 100mL round-bottom flask, dried dichloromethane is added as a reaction solvent, stirring is carried out for 15min at normal temperature, 0.48mL of dichloromethane solution containing 6.8mmol of acetyl chloride is slowly added dropwise under ice bath conditions, and reaction is carried out for 30min at normal temperature after dropwise addition. After 2h, the mixture was poured into ice water, the organic layer was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and petroleum ether: separating and purifying the ethyl acetate with a 10:1 column to obtain a compound 9;
(2) 1.3g (6.7mmol) of the compound 9 obtained in the step (1) was weighed into a 50mL round-bottomed flask, 7mL of DMF-DMA was added as a reactant and a solvent, and the mixture was refluxed for 1 hour, and the remaining DMF-DMA was distilled off under reduced pressure to obtain a compound 10. Taking 1.25g (5.0mmol) of the compound 10, adding 0.74mL (7.5mmol) of phenylhydrazine into 20mL of absolute ethyl alcohol, refluxing for 1h, evaporating the solvent, and separating and purifying by a silica gel column to obtain a compound 11.
(3) 4.4g (15mmol) of the compound 11 obtained in the step (2) was taken, and K was added2Cr2O7·2H2And refluxing O13.20 g (44.0mmol) in 35mL of glacial acetic acid for 2h, cooling to room temperature, pouring into ice water, and performing suction filtration and water washing to obtain a compound 12.
(4) 0.51g (1.5mmol) of the compound 12 obtained in the step (3) is taken out and added with 1.785mmol of 5b in 20mL of absolute ethanol, reflux reaction is carried out for 5h, the solvent is removed by evaporation under reduced pressure, chloroform extraction is carried out, the organic layer is collected, dried by anhydrous sodium sulfate and concentrated under reduced pressure, and the dichloromethane, methanol and 5 columns are separated and purified to obtain a compound 13 a.
(5) And (3) taking 1mmol of the compound 13a obtained in the step (4) into 2mL of absolute ethyl alcohol, dropwise adding 2mL of 4M HCl ethanol solution under ice-bath stirring, stirring overnight at room temperature until a large amount of solid appears, filtering, collecting the solid, washing with redistilled absolute ethyl alcohol for three times, and drying to obtain the compound 14 a. The yield was 48%.
1H NMR(300MHz,DMSO-d6)δ:8.41(t,J＝6.0Hz,2H),8.02(d,J＝6.0Hz,1H),7.95(d,J＝3.0Hz,1H),7.74(t,J＝9.0Hz,2H),7.18(d,J＝9.0Hz,5H),6.81(s,1H),4.01(s,2H),3.09-2.71(m,10H),1.65(s,12H).13C NMR(75MHz,DMSO-d6)δ163.71,163.50,141.04,139.71,139.12,134.93,132.08,131.49,130.38,130.17,130.00,129.56,128.46,128.06,128.02,124.70,122.96,122.85,111.45,46.84,46.35,46.24,38.46,25.26,24.52,23.62,23.05,22.97,22.85.ESI-MS m/z:553.53[M-4HCl+1]+.Elemental analysis for C33H44Cl4N6O2·0.1H2O:C,56.59；H,6.36；N,12.00；Found:C,56.78；H,6.39；N,12.17.
Example 2
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [3-3- (3-aminopropyl) -aminopropyl ] 1H-benzisoquinoline-1, 3(2H) -dione tetrahydrochloride (14b)
The synthesis and purification were the same as in example 1 except that 5a was used instead of 5b in step (4). The yield was 52%.
1H NMR(300MHz,DMSO-d6)δ:8.46(dd,J＝9.0,6.0Hz,2H),8.08(d,J＝9.0Hz,1H),7.98(d,J＝3.0Hz,1H),7.77(dd,J＝15.0,7.5Hz,2H),7.25-7.18(m,5H),6.83(s,1H),4.10(t,J＝6.0Hz,2H),3.01-2.88(m,10H),2.08-1.97(m,6H).13C NMR(75MHz,DMSO-d6)δ163.96,163.75,141.04,139.72,139.17,134.96,132.06,131.49,130.37,130.17,130.01,129.56,128.45,128.14,128.08,124.75,123.04,122.93,111.44,45.25,44.30,44.22,37.71,36.32,24.88,23.89,22.63.ESI-MS m/z:511.47[M-4HCl+1]+.Elemental analysis for C30H38Cl4N6O2:C,54.89；H,5.83；N,12.80；Found:C,54.73；H,6.18；N,12.73.
Example 3
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [4- (4-aminobutyl) -aminobutyl ] 1H-benzisoquinoline-1, 3(2H) -dione trihydrochloride (14c)
The synthesis and purification were the same as in example 1 except that 3d was used in place of 5b in step (4). The yield was 58%.
1H NMR(300MHz,DMSO-d6)δ:8.49-8.41(m,2H),8.12-8.03(m,1H),7.98(d,J＝3.0Hz,1H),7.77(dd,J＝13.5,7.5Hz,2H),7.25-7.17(m,5H),6.84(d,J＝3.0Hz,1H),4.05(s,2H),2.95-2.82(m,4H),2.79(d,J＝6.0Hz,2H),1.66(d,J＝18.0Hz,8H).13C NMR(75MHz,DMSO-d6)δ163.77,163.58,141.05,139.70,139.16,134.96,132.08,131.53,130.42,130.20,130.00,129.56,128.48,128.06,124.73,122.94,122.83,111.43,46.74,46.26,38.28,25.21,24.34,23.59,22.84.ESI-MS m/z:482.43[M-3HCl+1]+.Elemental analysis for C29H34Cl3N5O2·0.3H2O:C,58.41；H,5.85；N,11.74；Found:C,58.92；H,5.52；N,11.58.
Example 4
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [3- (4-aminobutyl) -aminopropyl ] 1H-benzisoquinoline-1, 3(2H) -dione trihydrochloride (14d)
The synthesis and purification were the same as in example 1 except that 3c was used in place of 5b in step (4). The yield was 61%.
1H NMR(300MHz,DMSO-d6)δ8.45(t,J＝7.5Hz,2H),8.07(d,J＝9.0Hz,1H),7.97(s,1H),7.77(dd,J＝12.0,6.0Hz,2H),7.24-7.17(m,5H),6.83(s,1H),4.05(s,2H),2.92(dq,J＝15.0,9.0Hz,6H),1.93(t,J＝9.0Hz,2H),1.68(s,4H).13C NMR(75MHz,DMSO-d6)δ163.80,163.59,141.07,139.68,139.18,134.96,132.09,131.55,130.46,130.21,129.99,129.56,128.48,128.10,128.02,124.75,122.91,122.79,111.42,46.96,44.23,36.37,25.16,23.93,23.60.ESI-MS m/z:468.43[M-3HCl+1]+.Elemental analysis for C28H32Cl3N5O2·1.2H2O:C,56.19；H,5.79；N,11.70；Found:C,56.16；H,5.73；N,11.98.
Example 5
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [4- (3-aminopropyl) -aminobutyl ] 1H-benzisoquinoline-1, 3(2H) -dione trihydrochloride (14e)
The synthesis and purification were the same as in example 1 except that 3b was used in place of 5b in step (4). The yield was 43%.
1H NMR(300MHz,DMSO-d6)δ8.46(t,J＝7.5Hz,2H),8.18(d,J＝9.0Hz,1H),7.97(s,1H),7.83-7.73(m,2H),7.32-7.15(m,5H),6.82(s,1lH),4.09(t,J＝6.0Hz,2H),2.98(t,J＝7.5Hz,2H),2.87(t,J＝6.0Hz,2H),2.81-2.74(m,2H),2.07-1.97(m,2H),1.69-1.53(m,4H).13C NMR(75MHz,DMSO-d6)δ163.95,163.73,141.04,139.75,139.15,134.96,132.09,131.47,130.34,130.17,130.05,129.56,128.46,128.18,128.05,124.75,123.10,123.00,111.46,46.31,45.21,38.47,37.76,24.89,24.51,22.99.ESI-MS m/z:468.43[M-3HCl+1]+.Elemental analysis for C28H32Cl3N5O2·H2O:C,56.53；H,5.76；N,11.77；Found:C,56.69；H,5.55；N,11.91.
Example 6
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [3- (3-aminopropyl) -aminopropyl ] 1H-benzisoquinoline-1, 3(2H) -dione trihydrochloride (14f)
The synthesis and purification were the same as in example 1 except that 3a was used instead of 5b in step (4). The yield was 70%.
1H NMR(300MHz,DMSO-d6)δ:8.54-8.39(m,2H),8.10(d,J＝9.0Hz,1H),7.99(d,J＝3.0Hz,1H),7.84-7.73(m,2H),7.33-7.16(m,5H),6.84(s,1H),4.11(t,J＝6.0Hz,2H),3.00-2.74(m,6H),2.02(m,4H).13C NMR(75MHz,DMSO-d6)δ163.96,163.75,141.03,139.75,139.15,134.95,132.08,131.46,130.34,130.16,130.05,129.56,128.46,128.19,128.04,124.75,123.11,123.01,111.46,45.37,44.27,37.75,36.56,24.93,24.16.ESI-MS m/z 454.40[M-3HCl+1]+.Elemental analysis for C27H30Cl3N5O2·0.8H2O:C,56.17；H,5.52；N,12.13；Found:C,56.39；H,5.86；N,12.30.
Example 7
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [3- (diethylamino) -propyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (14g)
The synthesis and purification were the same as in example 1 except that N, N-diethylpropanediamine was used in place of 5b in the step (4). The yield was 62%.
1H NMR(300MHz,Deuterium Oxide)δ8.08(d,J＝9.0Hz,1H),7.97(d,J＝3.0Hz,1H),7.91(d,J＝9.0Hz,1H),7.84(d,J＝9.0Hz,1H),7.42(t,J＝9.0Hz,1H),7.17(d,J＝9.0Hz,1H),6.98(t,J＝7.5Hz,1H),6.82(t,J＝7.5Hz,2H),6.72-6.61(m,3H),3.82(s,1H),3.21(p,J＝8.4,6.0Hz,6H),1.89(t,J＝9.0Hz,2H),1.30(t,J＝7.5Hz,6H).13C NMR(75MHz,Deuterium Oxide)δ164.30,164.03,140.77,138.93,138.30,134.62,132.60,131.83,130.23,129.48,128.87,127.92,127.64,127.19,124.26,121.13,120.82,110.92,49.09,47.36,37.39,22.05,8.16.ESI-MS m/z:453.42[M-2HCl+1]+.Elemental analysis for C28H30Cl2N4O2:C,64.00；H,5.75；N,10.66；Found:C,64.36；H,5.30；N,10.53.
Example 8
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [3- (dimethylamino) -propyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (14H)
The synthesis and purification were the same as in example 1 except that N, N-dimethylpropanediamine was used in place of 5b in step (4). The yield was 56%.
1H NMR(300MHz,DMSO-d6)δ:8.52-8.39(m,2H),8.07(d,J＝3.0Hz,1H),7.98(d,J＝3.0Hz,1H),7.85-7.71(m,2H),7.19-7.24(m,5H),6.83(d,J＝3.0Hz,1H),4.08(t,J＝7.5Hz,2H),3.15(dd,J＝6.0,9.0Hz,2H),2.72(s,6H),2.14-1.95(m,2H).13C NMR(75MHz,DMSO-d6)δ163.94,163.73,141.03,139.76,139.16,134.91,132.03,131.42,130.30,130.15,130.04,129.56,128.43,128.07,124.78,123.13,111.46,54.80,42.34,37.63,23.29.ESI-MS m/z:425.37[M-2HCl+1]+.Element analysis for C26H26Cl2N4O2·0.2CH3CH2OH:C,62.59；H,5.41；N,11.06；Found:C,62.62；H,5.17；N,11.26.
Example 9
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [2- (dimethylamino) -ethyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (14i)
The synthesis and purification were the same as in example 1 except that N, N-dimethylethylenediamine was used in place of 5b in step (4). The yield was 46%.
1H NMR(300MHz,Deuterium Oxide)δ:8.17(d,J＝6.0Hz,1H),8.00(d,J＝9.0Hz,1H),7.95(s,1H),7.93(s,1H),7.47(t,J＝7.5Hz,1H),7.29(d,J＝9.0Hz,1H),7.03(t,J＝7.5Hz,1H),6.90(t,J＝7.5Hz,2H),6.75-6.67(m,3H),4.23(t,J＝6.0Hz,2H),3.32(t,J＝6.0Hz,2H),2.97(s,6H).13C NMR(75MHz,Deuterium Oxide)δ167.16,166.93,143.28,141.63,140.79,137.47,135.46,134.57,133.09,132.15,131.56,131.46,130.54,130.19,129.90,126.86,123.60,123.24,113.35,57.58,45.77,37.70.ESI-MS m/z:411.36[M-2HCl+1]+.Elemental analysis for C25H24Cl2N4O2:C,62.12；H,5.00；N,11.59；Found:C,62.05；H,5.08；N,11.22.
Example 10
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [4- (morpholine) -butyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (14j)
The synthesis and purification were the same as in example 1 except that compound 7b was used in place of 5b in step (4). Yield: 67%.
1H NMR(300MHz,DMSO-d6)δ8.30(dd,J＝9.0,6.0Hz,2H),7.96(s,1H),7.93(s,1H),7.71-7.59(m,2H),7.15(s,5H),6.77(d,J＝3.0Hz,1H),3.93(d,J＝6.0Hz,4H),3.72(s,2H),3.38(d,J＝12.0Hz,2H),3.17-2.87(m,4H),1.75(s,2H),1.61(s,2H).13C NMR(75MHz,DMSO-d6)δ163.60,163.40,141.02,139.70,139.11,134.84,131.95,131.39,130.29,130.07,129.91,129.52,128.34,127.99,124.67,122.87,122.76,111.41,63.58,55.94,51.32,25.17,20.87.ESI-MS m/z:481.40[M-2HCl+1]+.Elemental analysis for C29H30Cl2N4O3·0.2H2O:C,62.53；H,5.50；N,10.06；Found:C,62.39；H,5.13；N,10.25.
Example 11
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [3- (hydroxy) -propyl ] 1H-benzisoquinoline-1, 3(2H) -dione (14k)
The synthesis and purification were the same as in example 1 except that 3-aminopropanol was used in place of 5b in step (4). Yield: 76 percent.
1H NMR(300MHz,Chloroform-d)δ:8.61(dd,J＝3.0,6.0Hz,1H),8.52(d,J＝9.0Hz,1H),8.22(dd,J＝6.0,3.0Hz,1H),7.90(d,J＝3.0Hz,1H),7.74-7.63(m,1H),7.57(d,J＝9.0Hz,1H),7.18(s,5H),6.68(d,J＝3.0Hz,1H),4.34(t,J＝7.5Hz,2H),3.60(s,2H),3.09(s,1H),2.21-1.89(m,2H).13C NMR(75MHz,Chloroform-d)δ164.65,164.45,140.62,139.39,138.75,132.18,131.92,130.64,130.17,129.47,129.08,127.64,127.60,124.19,122.57,122.52,110.95,58.93,36.96,30.96.ESI-MS m/z:398.35[M+1]+.Elemental analysis for C24H19N3O3·0.1H2O:C,72.20；H,4.85；N,10.53；Found:C,72.57；H,4.98；N,10.70.
Example 12
Synthesis of 6{3- (1-phenyl-1H-pyrazole) } -2- [2- (carboxy) -ethyl ] 1H-benzisoquinoline-1, 3(2H) -dione (14l)
The synthesis and purification were the same as in example 1 except that 3-aminopropionic acid was used in place of 5b in the step (4). The yield was 65%.
1H NMR(300MHz,Chloroform-d)δ8.61(d,J＝6.0Hz,1H),8.52(d,J＝6.0Hz,1H),8.20(d,J＝9.0Hz,1H),7.91(s,1H),7.69(t,J＝7.5Hz,1H),7.57(d,J＝6.0Hz,1H),7.18(s,5H),6.68(s,1H),4.51(s,2H),2.83(s,2H).13C NMR(75MHz,DMSO-d6)δ173.05,163.54,163.34,141.02,139.73,139.15,134.93,132.05,131.41,130.30,130.13,130.01,129.54,128.40,128.07,128.01,124.69 123.01,122.90,111.43,36.34,32.64.ESI-MS m/z:412.33[M+1]+.Elemental analysis for C24H17N3O4·0.5CH3CH2OH:C,69.12；H,4.64；N,9.67；Found:C,68.94；H,4.43；N,9.70.
Example 13
Synthesis of 6- [4- (4-aminoquinazoline) ] -2- [2- (2-dimethylamino) -ethyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (22a)
(1) Adding 1.00g (8.5mmol) of compound 15 into a 50mL round-bottom flask, then adding 3mL of DMF-DMA, carrying out reflux reaction for 3.5h, placing the product in a refrigerator, carrying out suction filtration after one night, and washing with anhydrous ether to obtain compound 16;
(2) 1.0g (6.5mmol) of compound 17 and K are taken2Cr2O7·2H2Placing 4.8g (16.2mmol) of O in a 50mL round-bottom flask, adding 10mL of glacial acetic acid as a solvent, refluxing for 8h, filtering, washing with water to be neutral, and drying to obtain a compound 18;
(3) 0.9g (5mmol) of Compound 18 obtained in step (2) was weighed into a 50mL round-bottom flask, and 5mL of concentrated H was added2SO4As a solvent, dropwise adding mixed acid prepared from 0.33mL of concentrated nitric acid (63 wt% -68 wt%) and 15mL of concentrated sulfuric acid (98 wt%) under the condition of ice-water bath cooling, reacting for 3h, pouring into ice water, performing suction filtration, washing to be neutral, and drying to obtain a compound 19;
(4) 1.2g (5.0mmol) of the compound 19 obtained in the step (3) was placed in a 50mL round-bottom flask, and 4.5g (20.0mmol) of SnCl was added2·2H2O and 3.3mL (40.0mmol) concentratedHydrochloric acid and 15mL of ethanol are used as reaction solvents, after refluxing for 3h, the mixture is filtered, filter cakes are washed by diethyl ether, and the mixture is dried to obtain a compound 20;
(5) taking 1.06g (5mmol) of the compound 20 obtained in the step (4) and 1.73g (10.0mmol) of the compound 16 in a 100mL round-bottom flask, adding 20mL of glacial acetic acid as a reaction solvent, carrying out reflux reaction for 5h, filtering while hot, and washing with water and DMF to obtain a compound 21;
(6) taking 0.551mg (1.5mmol) of the compound 21 obtained in the step (5) into a 50mL round-bottom flask, adding the mixture into 20mL absolute ethyl alcohol, refluxing and reacting 1.8mmol (158mg) of N, N-dimethylethylenediamine for 5 hours, evaporating the solvent, and separating and purifying by a silica gel column to obtain a compound 22 a;
(7) and (3) taking 1mmol of the compound 22a obtained in the step (6) into 5mL of absolute ethyl alcohol, dropwise adding 2mL of 4M HCl ethanol solution under ice-bath stirring, stirring overnight at room temperature until a large amount of solid appears, filtering, collecting the solid, washing with redistilled absolute ethyl alcohol for three times, and drying to obtain the compound 23 a. Yield: 48 percent.
1H NMR(300MHz,DMSO-d6)δ:(55％yield).1H NMR(300MHz,DMSO-d6)δ9.09-8.97(m,2H),8.92(d,J＝3.0Hz,1H),8.87(d,J＝3.0Hz,1H),8.50(d,J＝9.0Hz,2H),8.20-8.10(m,1H),8.01(d,J＝9.0Hz,1H),7.97-7.85(m,2H),4.42(s,2H),3.48(t,J＝6.0Hz,2H),2.91(s,6H).13C NMR(75MHz,DMSO-d6)δ164.39,164.13,160.52,151.66,139.65,136.94,136.06,134.79,132.02,131.10,129.35,128.47,126.18,125.31,123.29,122.63,120.69,114.11,55.18,43.11,35.72.ESI-MS m/z:412.30[M-2HCl+1]+.Elemental analysis for C24H23Cl2N5O2·1.5H2O·0.4CH3CH2OH:C,56.22；H,5.40；N,13.22；Found:C,56.32；H,5.66；N,13.28.
Example 14
Synthesis of 6- [4- (4-aminoquinazoline) ] -2- [2- (3-dimethylamino) -propyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (22b)
The synthesis and purification process was the same as in example 13 except that N, N-dimethylpropylenediamine was used in place of N, N-dimethylethylenediamine in step (6). Yield: 58 percent.
1H NMR(300MHz,DMSO-d6)δ8.96(s,1H),8.90-8.75(m,3H),8.42-8.46(m,2H),8.12(t,J＝9.0Hz,1H),7.96-7.80(m,3H),4.11(t,J＝6.0Hz,2H),3.34-3.05(m,2H),2.75(s,6H),2.01-2.11(m,2H).13C NMR(75MHz,DMSO-d6)δ164.10,163.80,160.35,151.60,139.50,136.97,135.88,134.69,131.95,131.10,129.42,128.47,128.29,128.20,125.97,124.97,123.06,122.37,120.65,113.94,54.97,42.57,37.54,23.39.ESI-MS m/z:426.35[M-2HCl+1]+.Elemental analysis for C25H25Cl2N5O2·2.8H2O:C,54.71；H,5.62；N,12.76；Found:C,54.85；H,5.69；N,12.67.
Example 15
Synthesis of 6- [4- (4-aminoquinazoline) ] -2- [ (3-amino) -propyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (22c)
The synthesis and purification were the same as in example 13 except that in step (6), N-dimethylethylenediamine was replaced with 1 a. Yield: 42 percent.
1H NMR(300MHz,DMSO-d6)δ8.60–8.54(m,3H),8.50(d,J＝9.0Hz,1H),8.28(t,J＝9.0Hz,2H),8.19(d,J＝3.0Hz,1H),8.07–7.90(m,3H),7.84–7.71(m,2H),4.14(t,J＝6.0Hz,2H),2.89(t,J＝6.0Hz,2H),2.00(t,J＝7.5Hz,2H).ESI-MS m/z:398.31[M-2HCl+1]+.Elemental analysis for C23H21Cl2N5O2·3.5H2O:C,51.79；H,5.29；N,13.13；Found:C,51.73；H,5.58；N,13.26.
Example 16
Synthesis of 6- [4- (4-aminoquinazoline) ] -2- [ (3-morpholinyl) -propyl ] 1H-benzisoquinoline-1, 3(2H) -dione dihydrochloride (22d)
The synthesis and purification were carried out in the same manner as in example 13 except that in step (6), N-dimethylethylenediamine was replaced with 7 a. Yield: 56 percent.
1H NMR(300MHz,DMSO-d6)δ9.01(s,1H),8.97-8.86(m,3H),8.50(d,J＝9.0Hz,2H),8.14(t,J＝9.0Hz,1H),8.01-7.88(m,3H),4.15(t,J＝6.0Hz,2H),3.94(d,J＝12.0Hz,2H),3.72(t,J＝12.0Hz,2H),3.40(d,J＝12.0Hz,2H),3.28-3.18(m,2H),3.04-3.08(m,2H),2.11-2.19(m,2H).13C NMR(75MHz,DMSO-d6)δ164.12,163.86,160.31,151.98,140.51,136.72,136.28,134.64,132.11,130.95,129.20,128.47,128.27,128.00,126.04,125.06,123.27,122.62,121.39,114.25,63.68,54.28,51.41,37.66,22.58.ESI-MS m/z:468.34[M-2HCl+1]+.Elemental analysis for C27H27Cl2N5O3·2.3H2O:C,55.73；H,5.47；N,12.04；Found:C,55.64；H,5.49；N,11.95.
Test example 1
Evaluation of biological Activity
The in vitro tumor cell growth inhibition activity of the compound is determined: the compounds prepared in examples 1-23 were selected, and three tumor cell lines, MDA-MB-231 (breast cancer cells), HCT-116 (human colon cancer cells) and HepG2 (human liver cancer cells), were taken in logarithmic phase, and the representative drug aminonaftifide was used as a control, and 5000-8000 cells per well were embedded in a 96-well plate at a concentration of 90. mu.L/well. After 24h incubation, 10. mu.M and 30. mu.M samples were added, with four replicate wells for each cell line and each concentration, at 37 ℃ and 5% CO2Culturing for 48h, adding 50 μ L of MTT, culturing for 4h, discarding supernatant, adding 100 μ L of DSMO into each well, shaking gently for 15min, and measuring absorbance A at 570nm with microplate reader. The inhibition rate of the test substance on the growth of tumor cells was calculated according to the formula (inhibition rate of tumor cell growth (%) (OD control-OD experiment)/(OD control-OD blank) × 100%), and the experiment was repeated three times. The results are shown in Table 1.
TABLE 1 inhibitory Activity of test substances on the growth of different tumor cells
As can be seen from Table 1, the two series of compounds of the naphthalimide-polyamine conjugate provided by the invention have certain inhibitory activity on tumor cell strains HCT-116, HepG2 and MDA-MB-231. For example, the compounds 14a, 14c, 14d, 14f, 23b have better inhibitory activity and higher inhibition rate on the three tumor cells, for example, the compound 14a has the inhibition rate of more than 90% on three tumor cell lines of HCT-116, HepG2 and MDA-MB-231 at low concentration (10 muM) and high concentration (30 muM), and the inhibition rate is far higher than that of the positive control aminonaftifine. The 14a, 14c to 14f compounds provided by the invention have higher inhibition rates on three tumor cell strains, namely HCT-116, HepG2 and MDA-MB-231 than positive control aminonaftifide at low concentration (10 mu M); at high concentrations (30 μ M), the inhibition rates of compounds 14a to 14f were all higher than that of aminonaftifide for all three tumor cell lines. And the length of a side chain and the number of nitrogen-containing atoms in the phenylpyrazole modified naphthalimide-polyamine conjugate both have influence on the in vitro antitumor activity. The inhibition rate of the quinazoline modified naphthalimide-polyamine conjugate 23a on HCT-116 tumor cells is higher than that of the positive control aminonaftifide at low concentration (10 mu M) and high concentration (30 mu M). The compound 23b has higher inhibition rate on tumor cell lines HCT-116, HepG2 and MDA-MB-231 than aminonaftifide at high concentration (30. mu.M).
In conclusion, the naphthalimide-polyamine conjugate provided by the invention has certain inhibitory activity on tumor cell strains HCT-116, HepG2 and MDA-MB-231, shows good development potential, can be further developed as a potential antitumor drug lead compound, and provides a new direction for development of antitumor drugs.
The above embodiments are only preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, and any insubstantial changes and substitutions made by those skilled in the art based on the present invention are within the protection scope of the present invention.
Claims (5)
1. A naphthalimide-polyamine conjugate having the general structural formula i:
wherein R is phenylpyrazole or amino-quinazoline, q is 1, 2 or 3, and X is an integer of 0 to 4;
when R is phenylpyrazole, the naphthalimide-polyamine conjugate has the structural general formula I-1:
wherein R is2Is selected from
when R is amino-quinazoline, the naphthalimide-polyamine conjugate has a general structural formula I-2:
wherein R is2Is composed of
2. A process for the synthesis of compounds of formula i-1 according to claim 1, characterized in that it comprises the following steps:
(1) adding the compound 8 into a reaction container, and adding aluminum trichloride and acetyl chloride solution which take dichloromethane as a solvent to react to prepare a compound 9;
(2) adding the compound 9 obtained in the step (1) into a DMF-DMA solution for refluxing to prepare a compound 10, and then reacting with phenylhydrazine in an ethanol solution to prepare a compound 11;
(3) refluxing the compound 11 obtained in the step (2) with potassium dichromate under the condition that acetic acid is used as a solvent to prepare a compound 12;
(4) reacting the compound 12 obtained in the step (3) with a nitrogen-containing compound to prepare a compound 13;
(5) reacting the compound 13 obtained in the step (4) with 4M hydrochloric acid in absolute ethyl alcohol to obtain a naphthalimide-polyamine conjugate 14 with a structure shown in a general formula I-1;
wherein q is 1, 2 or 3, X is an integer from 0 to 4, R2Is selected from
N and k are 1 or 2.
3. A process for the synthesis of compounds of formula i-2 according to claim 1, characterized in that it comprises the following steps:
(1) taking DMF-DMA as a solvent, and carrying out reflux reaction on the compound 15 to obtain a compound 16;
(2) glacial acetic acid is used as a solvent, and the compound 17 is subjected to K2Cr2O7Oxidizing to obtain a compound 18;
(3) carrying out nitration reaction on the compound 18 obtained in the step (2) in a concentrated sulfuric acid solution to obtain a compound 19;
(4) reducing the compound 19 obtained in the step (3) by tin dichloride under an acidic condition to obtain a compound 20;
(5) reacting the compound 20 obtained in the step (4) with the compound 16 obtained in the step (1) under the condition of using glacial acetic acid as a solvent to obtain a compound 21;
(6) reacting the compound 21 obtained in the step (5) with a nitrogen-containing compound to obtain a compound 22;
(7) reacting the compound 22 obtained in the step (6) with 4M hydrochloric acid in absolute ethyl alcohol to obtain a naphthalimide-polyamine conjugate 23 with a structure shown in a general formula I-2;
wherein q is 1, 2 or 3, R2Is composed of
X is an integer of 0 to 4.
4. Use of the naphthalimide-polyamine conjugate of claim 1 in the preparation of an anti-tumor medicament.
5. The use of claim 4, wherein the medicament is a medicament against human colon, liver, or breast cancer.
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